The long-term objective of this proposal is to study the molecular mechanisms that underlie itch sensation at the spinal level. Although acute itch serves as a defense mechanism, chronic itch or pruritus represents a significant clinical problem for which no effective drugs are available. The dorsal spinal cord neurons are essential in processing, integrating and relaying itch information from the periphery to the brain. The molecular mechanisms underlying itch sensation in the spinal cord, however, are not well understood. We have recently shown that gastrin-releasing peptide receptor (GRPR), a mammalian homologue of bombesin-like peptide receptor family, has an important role in mediating itch sensation in the spinal cord. In contrast, GRPR is not required for pain sensation. GRPR thus is the first itch-specific molecule identified in the central nervous system. Recently, we also found that neuromedin B receptor (NMBR), the second mammalian bombesin-like peptide receptor, may also play a role in mediating itch sensation. In this proposal, we would like to study the roles of GRPR and NMBR in the transmission of itch and pain signals. In aim 1, we will test the hypothesis that NMBR has a role in mediating itch sensation in the spinal cord, and determine whether NMBR and GRPR have redundant function in this aspect. Both pharmacological and genetic approaches will be used to test this hypothesis. Aim 2 will determine whether NMBR is required for pain sensation and whether NMBR and GRPR may have redundant functions in pain by examining pain behaviors of NMBR mutant and NMBR/GRPR double mutant mice and by pharmacological studies. Aim 3 will test the hypothesis that spinal morphine-induced pruritus is dependent on the GRPR/NMBR signaling pathways. In aim 4, we will examine the roles of GRPR/NMBR+ cells in itch sensation by ablating GRPR/NMBR+ cells in the spinal cord followed by behavioral experiments. The proposed studies should not only delineate the roles of GRPR and NMBR but also of neurons expressing these receptors in itch sensation in the spinal cord. Together, our studies will unravel the central mechanisms underlying itch sensation and pave the way for designing new therapeutic strategy to treat chronic pruritus.